Atomoxetine (ATX) is a non-stimulant drug used in the treatment of attention-deficit/hyperactivity disorder (ADHD) and is a selective norepinephrine reuptake inhibitor. It has been shown that ATX has additional effects beyond the inhibition of norepinephrine reuptake, affecting several signal transduction pathways and alters gene expression. Here, we study alterations in oxidative stress and mitochondrial function in human differentiated SH-SY5Y cells exposed over a range of concentrations of ATX. We found that the highest concentrations of ATX in neuron-like cells, caused cell death and an increase in cytosolic and mitochondrial reactive oxygen species, and alterations in mitochondrial mass, membrane potential and autophagy. Interestingly, the dose of 10 μM ATX increased mitochondrial mass and decreased autophagy, despite the induction of cytosolic and mitochondrial reactive oxygen species. Thus, ATX has a dual effect depending on the dose used, indicating that ATX produces additional active therapeutic effects on oxidative stress and on mitochondrial function beyond the inhibition of norepinephrine reuptake.

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The psychostimulant methylphenidate (MPH) is the first-line pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD), but has numerous adverse side effects. The PPARγ receptor agonist pioglitazone (PIO) is known to improve mitochondrial bioenergetics and antioxidant capacity, both of which may be deficient in ADHD, suggesting utility as an adjunct therapy. Here, we assessed the effects of PIO on ADHD-like symptoms, mitochondrial biogenesis and antioxidant pathways in multiple brain regions of neonate rats with unilateral striatal lesions induced by 6-hydroxydopamine (6-OHDA) as an experimental ADHD model. Unilateral striatal injection of 6-OHDA reduced ipsilateral dopaminergic innervation by 33% and increased locomotor activity. This locomotor hyperactivity was not altered by PIO treatment for 14 days. However, PIO increased the expression of proteins contributing to mitochondrial biogenesis in the striatum, hippocampus, cerebellum and prefrontal cortex of 6-OHDA-lesioned rats. In addition, PIO treatment enhanced the expression of the phase II transcription factor Nrf2 in the striatum, prefrontal cortex and cerebellum. In contrast, no change in the antioxidant enzyme catalase was observed in any of the brain regions analyzed. Thus, PIO may improve mitochondrial biogenesis and phase 2 detoxification in the ADHD brain. Further studies are required to determine if different dose regimens can exert more comprehensive therapeutic effects against ADHD neuropathology and behavior.

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